Converging evidence from years of intensive research has implicated that a disorder of brain norepinephrine and/or serotonin occurs in major depression. However, the basic neurobiology of major depression has not yet been elucidated. The goal of this research is test the hypothesis that a distinct constellation of neurochemical/neuroanatomical deficits occurs in the noradrenergic system (in particular, the locus coeruleus) in major depression. Experiments are designed to address the issues of (1) the precise neurochemical and/or neuroanatomical alterations and (2) the specificity of alterations with respect to psychiatric illness. To address the first issue, concentrations of a number of proteins and substances will be measured throughout the locus coeruleus, and in a major limbic projection area (amygdala) in post-mortem brains from subjects with major depression and from psychiatrically normal control subjects. In particular, a number of noradrenergic and non-noradrenergic proteins which are sites of action of antidepressant drugs will be studied, along with proteins of which levels are modulated in the locus coeruleus by antidepressant treatment. Preliminary findings demonstrates that noradrenergic cell number is a major determinant of noradrenergic protein concentration in the locus coeruleus. Furthermore, cell loss in the locus coeruleus is associated with aging, Alzheimer's disease, and Parkinson's disease. Thus, if cell number in locus coeruleus is altered in psychiatric disease, such a change could complicate measurements of noradrenergic proteins in the locus coeruleus or lead to misinterpretation of neurochemical alterations in the locus coeruleus from major depressives. Thus, noradrenergic neuron density and number will be estimated stereologically in all subjects in parallel with neurochemical measurements. To address the issue of specificity, 4 groups of subjects will be studied: 1) no psychiatric diagnosis, age-matched control subjects dying of natural or accidental causes, 2) suicide victims with major depression, 3) non-suicide subjects with major depression, and 4) suicide victims with Axis I diagnoses other than major depression. This research will extend and clarify major findings of research in the first grant period. Elucidation of the biochemical and/or anatomical alterations of locus coeruleus neurons associated with major depression may yield important information for the development of more effective treatments for this devastating disorder.